This publication, an update to the previous guidance (2009), was produced by leading endocrinologists specialising in support for transgender adults and adolescents from the US, Belgium, and the Netherlands.

The guidelines are endorsed by the world’s leading centres for evidence based practice: the American Association of Clinical Endocrinologists, the American Society of Andrology, the European Society for Pediatric Endocrinology, the European Society of Endocrinology, the Pediatric Endocrine Society, and the World Professional Association for Transgender Health.

In short, the Endocrine Society represents the global medical consensus on the clinical treatment of transgender adults and adolescents.

Here, we will respond in detail to this guidance in the following three sections:

Section A: A summary of the guidance as it applies to transgender adolescents, including factors underpinning gender identity; diagnosis; prescription; eligibility criteria; consent; age of treatment and risk factors.

Section B: We raise questions which are either unclear within the guidance or were not covered as out of scope.

Section C: Concludes with concerns in seven areas of the guidance and provides suggestions for amendment or further research.

Section A: Summary

i) Gender identity has a “durable biological underpinning”

From the position paper:

“The medical consensus in the late 20th century was that transgender and gender incongruent individuals suffered a mental health disorder termed “gender identity disorder.” Gender identity was considered malleable and subject to external influences. Today, however, this attitude is no longer considered valid. Considerable scientific evidence has emerged demonstrating a durable biological element underlying gender identity. Individuals may make choices due to other factors in their lives, but there do not seem to be external forces that genuinely cause individuals to change gender identity.

Although the specific mechanisms guiding the biological underpinnings of gender identity are not entirely understood, there is evolving consensus that being transgender is not a mental health disorder. Such evidence stems from scientific studies suggesting that: 1) attempts to change gender identity in intersex patients to match external genitalia or chromosomes are typically unsuccessful; 2) identical twins (who share the exact same genetic background) are more likely to both experience transgender identity as compared to fraternal (non-identical) twins; 3) among individuals with female chromosomes (XX), rates of male gender identity are higher for those exposed to higher levels of androgens in utero relative to those without such exposure, and male (XY)-chromosome individuals with complete androgen insensitivity syndrome typically have female gender identity 6; and 4) there are associations of certain brain scan or staining patterns with gender identity rather than external genitalia or chromosomes

In summary, although there is much that is still unknown with respect to gender identity and its expression, compelling studies support the concept that biologic factors, in addition to environmental factors, contribute to this fundamental aspect of human development.

Data are strong for a biological underpinning to gender identity”

ii) Treatment is medically necessary

“These recommendations include evidence that treatment of gender dysphoria/incongruence is medically necessary and should be covered by insurance”

iii) Counselling can support social transition

“During social transitioning, the person’s feelings about the social transformation (including coping with the responses of others) is a major focus of the counseling.”

iv) Recommend puberty blockers

“We suggest that adolescents who meet diagnostic criteria for GD/gender incongruence, fulfill criteria for treatment, and are requesting treatment should initially undergo treatment to suppress pubertal development

These recommendations place a high value on avoiding an unsatisfactory physical outcome when secondary sex characteristics have become manifest and irreversible, a higher value on psychological well-being, and a lower value on avoiding potential harm from early pubertal suppression.”

vi) Diagnosis

“For children and adolescents, an MHP [mental health professional] who has training/experience in child and adolescent gender development (as well as child and adolescent psychopathology) should make the diagnosis, because assessing GD/gender incongruence in children and adolescents is often extremely complex.

For adolescents, the diagnostic procedure usually includes a complete psychodiagnostic assessment and an assessment of the decision-making capability of the youth. An evaluation to assess the family’s ability to endure stress, give support, and deal with the complexities of the adolescent’s situation should be part of the diagnostic phase”

A strong desire to be rid of one’s primary and/or secondary sex characteristics because of a marked incongruence with one’s experienced/expressed gender (or in young adolescents, a desire to prevent the development of the anticipated secondary sex characteristics)

A strong desire for the primary and/or secondary sex characteristics of the other gender

A strong desire to be of the other gender (or some alternative gender different from one’s designated gender)

A strong desire to be treated as the other gender (or some alternative gender different from one’s designated gender)

A strong conviction that one has the typical feelings and reactions of the other gender (or some alternative gender different from one’s designated gender)

B. The condition is associated with clinically significant distress or impairment in social, occupational, or other important areas of functioning.

Specify if:

The condition exists with a disorder of sex development.

The condition is posttransitional, in that the individual has transitioned to full-time living in the desired gender (with or without legalization of gender change) and has undergone (or is preparing to have) at least one sex-related medical procedure or treatment regimen—namely, regular sex hormone treatment or gender reassignment surgery confirming the desired gender (e.g., penectomy, vaginoplasty in natal males; mastectomy or phalloplasty in natal females).

Table 3. ICD-10 Criteria for Transsexualism (F64.0) has three criteria:

The desire to live and be accepted as a member of the opposite sex, usually accompanied by the wish to make his or her body as congruent as possible with the preferred sex through surgery and hormone treatments.

The transsexual identity has been present persistently for at least 2 y.

The disorder is not a symptom of another mental disorder or a genetic, DSD, or chromosomal abnormality

vii) Criteria for blockers

Adolescents are eligible for GnRH agonist treatment if:

1. A qualified MHP has confirmed that:

the adolescent has demonstrated a long-lasting and intense pattern of gender nonconformity or gender dysphoria (whether suppressed or expressed),

gender dysphoria worsened with the onset of puberty,

any coexisting psychological, medical, or social problems that could interfere with treatment (e.g., that may compromise treatment adherence) have been addressed, such that the adolescent’s situation and functioning are stable enough to start treatment,

the adolescent has sufficient mental capacity to give informed consent to this (reversible) treatment,

2. And the adolescent:

has been informed of the effects and side effects of treatment (including potential loss of fertility if the individual subsequently continues with sex hormone treatment) and options to preserve fertility,

has given informed consent and (particularly when the adolescent has not reached the age of legal medical consent, depending on applicable legislation) the parents or other caretakers or guardians have consented to the treatment and are involved in supporting the adolescent throughout the treatment process,

3. And a pediatric endocrinologist or other clinician experienced in pubertal assessment

agrees with the indication for GnRH agonist treatment,

has confirmed that puberty has started in the adolescent (Tanner stage $G2/B2),

has confirmed that there are no medical contraindications to GnRH agonist treatment.

viii) Criteria for gender affirming hormone treatment

Adolescents are eligible for subsequent sex hormone treatment if:

1. A qualified MHP has confirmed:

the persistence of gender dysphoria,

any coexisting psychological, medical, or social problems that could interfere with treatment (e.g., that may compromise treatment adherence) have been addressed, such that the adolescent’s situation and functioning are stable enough to start sex hormone treatment,

the adolescent has sufficient mental capacity (which most adolescents have by age 16 years) to estimate the consequences of this (partly) irreversible treatment, weigh the benefits and risks, and give informed consent to this (partly) irreversible treatment,

2. And the adolescent:

has been informed of the (irreversible) effects and side effects of treatment (including potential loss of fertility and options to preserve fertility),

has given informed consent and (particularly when the adolescent has not reached the age of legal medical consent, depending on applicable legislation) the parents or other caretakers or guardians have consented to the treatment and are involved in supporting the adolescent throughout the treatment process,

3. And a pediatric endocrinologist or other clinician experienced in pubertal induction:

agrees with the indication for sex hormone treatment,

has confirmed that there are no medical contraindications to sex hormone treatment

ix) High satisfaction rates for cross-sex hormone treatment

“Follow-up studies in adults meeting these criteria indicate a high satisfaction rate with treatment. However, the quality of evidence is usually low. A few follow-up studies on adolescents who fulfilled these criteria also indicated good treatment results”

x) Cross-sex hormones by informed consent

“Clinicians may add gender-affirming hormones after a multidisciplinary team has confirmed the persistence of gender dysphoria/gender incongruence and sufficient mental capacity to give informed consent to this partially irreversible treatment. Most adolescents have this capacity by age 16 years old. We recognize that there may be compelling reasons to initiate sex hormone treatment prior to age 16 years, although there is minimal published experience treating prior to 13.5 to 14 years of age.”

xi) Gradually increasing dose of cross-sex hormones

“In adolescents who request sex hormone treatment (given this is a partly irreversible treatment), we recommend initiating treatment using a gradually increasing dose schedule after a multidisciplinary team of medical and MHPs has confirmed the persistence of GD/gender incongruence and sufficient mental capacity to give informed consent, which most adolescents have by age 16 years.”

xii) Hormone treatment is safe

“Medical intervention for transgender individuals (including both hormone therapy and medically indicated surgery) is effective, relatively safe (when appropriately monitored), and has been established as the standard of care.

The data are strong for the relative safety of hormone treatment (when appropriately monitored medically)

Federal and private insurers should cover such interventions”

xiii) Fertility counselling prior to blockers

“We recommend that clinicians inform and counsel all individuals seeking gender-affirming medical treatment regarding options for fertility preservation prior to initiating puberty suppression in adolescents and prior to treating with hormonal therapy of the affirmed gender in both adolescents and adults.”

xiv) Fertility

“Treating early pubertal youth with GnRH analogs will temporarily impair spermatogenesis and oocyte maturation. Given that an increasing number of transgender youth want to preserve fertility potential, delaying or temporarily discontinuing GnRH analogs to promote gamete maturation is an option. This option is often not preferred, because mature sperm production is associated with later stages of puberty and with the significant development of secondary sex characteristics.”

xv) Insufficient evidence to guide on minimum age for chest surgery

“We suggest that clinicians determine the timing of breast surgery for transgender males based upon the physical and mental health status of the individual. There is insufficient evidence to recommend a specific age requirement.”

xvii) Lack of support may interfere with positive surgery outcomes

“Literature on postoperative regret suggests that besides poor quality of surgery, severe psychiatric comorbidity and lack of support may interfere with positive outcomes”

xviii) Significant areas where further research is needed to optimise care, but this research will take a long time

“The gaps in knowledge to optimize care over a lifetime are profound. Comparative effectiveness research in hormone regimens is needed to determine:

The best endocrine and surgical protocols, as it is not yet known if certain regimens are safer or more effective than others;

Whether there are cardiovascular, malignancy, or other long-term risks from hormone interventions, particularly as the transgender individual ages.

The biological processes underlying gender identity

Strategies for fertility preservation

To successfully establish and enact these protocols requires long-term, large-scale studies across countries that employ the same care protocols.

Increased funding for national research programs is needed to close the gaps in knowledge regarding transgender medical care and should be made a priority” (Endocrine Society, Position Statement, 2017)

Section B: Questions on guidance

We have seven questions on areas in the guidance which are either unclear or were not covered as out of scope.

1 – Pre-pubertal children

“We recommend against puberty blocking and gender-affirming hormone treatment in prepubertal children with GD/gender incongruence.”

This recommendation is described as: “a strong recommendation in the face of low-quality evidence”, as “the task force placed a high value on avoiding harm with gender-affirming hormone therapy in pre-pubertal children with GD/gender incongruence”

Question area 1:

Surely no one is advocating for any medical prescription for pre-pubertal children in which case this statement is moot? Is this perhaps instead referring to prescription at the first onset of puberty? Further clarity is required here.

2 – Role of Mental Health Professional (MHP) in social transition

“We advise that decisions regarding the social transition of prepubertal youths with GD/gender incongruence are made with the assistance of an MHP or another experienced professional.”

Question area 2:

Can greater clarity be provided on which “other experienced professional” is suitable to “assist in decision making”? Is a MHP required, what is their role, and why are they necessary for making decisions on social transition? How would a MHP be defined?

We also note there is no evidence provided for such a requirement. Anecdotally many young children socially transition without any support to the child from a mental health professional (though we do see the value of support to the parent and wider family from a MHP or other professional to cope with conflicting emotions and stress of a ‘family in transition’. On this issue, we note the needs of parents, carers and family members are absent from this document).

3 – Monitoring onset of puberty

“Clinicians can use pubertal LH and sex steroid levels to confirm that puberty has progressed sufficiently before starting pubertal suppression. Ultrasensitive sex steroid and gonadotropin assays will help clinicians document early pubertal changes.”

Question area 3:

How frequently should LH and sex steroid levels be monitored? In which countries / locations is this carried out as standard? When does monitoring start? Can clarity be given on the correspondence between LH/sex steroid levels and tanner stage? At what level of LH/sex steroid do adolescents become eligible for GnRH agonists?

4 – Side effects of blockers

“Individuals may also experience hot flashes, fatigue, and mood alterations as a consequence of pubertal suppression. There is no consensus on treatment of these side effects in this context.

Acne, headache, hot flashes, and fatigue were other frequent side effects.”

Question area 4:

In countries without age based restrictions on cross sex hormone prescription, are blocker related side effects taken into consideration when making decisions on whether and when to proceed to cross sex hormones?

“MHPs should diagnose GD/gender incongruence prior to gender affirming hormone treatment “to make a distinction between GD/ gender incongruence and conditions that have similar features. Examples of conditions with similar features are body dysmorphic disorder, body identity integrity disorder (a condition in which individuals have a sense that their anatomical configuration as an able-bodied person is somehow wrong or inappropriate) (66), or certain forms of eunuchism (in which a person is preoccupied with or engages in castration and/or penectomy for reasons that are not gender identity related)”

Question area 5:

It seems that the primary reason for a mental health professional led diagnosis is to distinguish GD/GI from these other conditions. What data is available on the numbers of children presenting for gender affirming hormone treatment who are instead diagnosed with one of these three other conditions?

6 – Blockers always required before cross sex hormone treatment

The criteria for sex hormone treatment refers to “subsequent cross sex hormone treatment”. The implication of this statement is that adolescents will proceed to sex hormone treatment only after having received GnRH agonist treatment.

Question area 6:

How are adolescents already at late stage of puberty treated upon referral? Is prescription of blockers on their own required before prescription of cross sex hormones even for youth already in late puberty?

Question area 7:

To a lay reader, table 10 is not informative. It would be useful to know both the actual risk and two comparisons Eg when considering the risk of coronary artery disease for a transgender female it would be useful to understand i) what the level of risk is for a trans female on estrogen (eg 1/10,000) and how this compares both to ii) a trans female not on estrogen (eg 1/9,000) and iii) a cis female (eg 1/9,000). (The numbers in this example are fictitious). Is risk information in this format available?

Section C: Concerns with guidance

There are seven areas of the guidance that we find to be problematic as described below.

1. Reference to gender non-conforming children

The section on areas for further research mentions the need for further research on “The optimal approaches to gender non-conforming children”.

Concern 1:

The vast majority of gender non-conforming children have no need of input from an endocrinologist, so the inclusion of this statement is strange. Why not focus future research on optimal approaches for transgender children?

2. Harm of second social transition

If children have completely socially transitioned, they may have great difficulty in returning to the original gender role upon entering puberty (Source: Steensma TD, Biemond R, de Boer F, Cohen-Kettenis PT. Desisting and persisting gender dysphoria after childhood: a qualitative follow-up study. Clin Child Psychol Psychiatry. 2011;16(4):499–516.

A more measured assessment of the evidence base, which does not over-reach in its conclusions, is found in the new Australian guidelines, “The number of children in Australia who later socially transition back to their gender assigned at birth is not known, but anecdotally appears to be low, and no current evidence of harm in doing so exists”.

3. Social transition impacting persistence

“However, social transition (in addition to GD/gender incongruence) has been found to contribute to the likelihood of persistence.”

Concern 3:

Where is the evidence for this finding? What is the counter factual? Evidence that socially transitioned children are more likely to be transgender than children who do not socially transition, is not evidence that social transition makes children transgender who would not otherwise have persisted. It is very possible (probable in my opinion and experience) that only the most persistent, insistent, consistent children socially transition, so these children are unlikely to be the same children as those who do not socially transition. This statement is not supported by robust evidence.

4. Inclusion of debunked desistence statistics

“However, the large majority (about 85%) of prepubertal children with a childhood diagnosis did not remain GD/ gender incongruent in adolescence (Source: Steensma TD, Kreukels BP, de Vries AL, Cohen-Kettenis PT. Gender identity development in adolescence. Horm Behav. 2013; 64(2):288–297.

Prospective follow-up studies show that childhood GD/gender incongruence does not invariably persist into adolescence and adulthood (so-called “desisters”). In adolescence, a significant number of these desisters identify as homosexual or bisexual. It may be that children who only showed some gender nonconforming characteristics have been included in the follow-up studies, because the DSM-IV text revision criteria for a diagnosis were rather broad. However, the persistence of GD/gender incongruence into adolescence is more likely if it had been extreme in childhood (41, 42). With the newer, stricter criteria of the DSM-5 (Table 2), persistence rates may well be different in future studies.”

Concern 4:

Within the guidelines the discussion of desistence is inconsistent. In one section the unreliability of the desistance rates evidence base is acknowledged, but in another section the 85% desistance figure is confidently stated without any qualification. Desistence rates have a extremely significant impact on public, media, community, practitioner and parental approaches to a transgender child. Desistance rates have a direct impact on policy (these flawed desistance rates are currently quoted in the consultation documents on whether to allow under 16s rights under the reformed Scottish Gender Recognition Act). Stating as fact desistance rates that are not based on robust evidence is unethical, and if, as many believe, these rates are incorrect, is harmful.

5. Can only assess persistence (and prescribe blockers) after an adolescent has experienced the first stage of natal puberty

“At the present time, clinical experience suggests that persistence of GD/gender incongruence can only be reliably assessed after the first signs of puberty.”

“Adolescents with GD/gender incongruence should experience the first changes of their endogenous spontaneous puberty, because their emotional reaction to these first physical changes has diagnostic value in establishing the persistence of GD/gender incongruence (85).” (Listed source: Delemarre-van de Waal HA, Cohen-Kettenis PT. Clinical management of gender identity disorder in adolescents: a protocol on psychological and paediatric endocrinology aspects. Eur J Endocrinol. 2006;155:S131–S137.”

Criteria for prescription of blockers includes “gender dysphoria worsened with the onset of puberty”.

Concern 5:

The claim that persistence can only be assessed after a youth has experienced the first stages of puberty has one listed reference in the Endocrine guidance – de Waal and Cohen Kettenis 2006. However, de Waal’s paper does not contain this claim, nor any evidence for this claim. Instead, de Waal and Cohen Kettenis 2006 states that the suppression of puberty using GnRHa is a “very helpful diagnostic aid”, in that it allows time for open exploration. Notably there is no discussion in this paper of the diagnostic value of waiting for the first physical changes of puberty.

The endocrine guidelines contains no reference to any evidence that the early stage of puberty is diagnostic. Why therefore is this unsubstantiated recommendation included?

(We are aware of one deeply flawed and unreliable Steensma publication that over states conclusions on puberty and persistence, which will be the focus of our next research blog – this Steensma paper is not included in the references for the Endocrine guidance)

The belief that GD/GI can only be reliably assessed after a youth has experienced (and been distressed by) the first stage of puberty results in a requirement for transgender children to have to endure the first stage of puberty (and distress at these physical changes) before being deemed eligible for blockers.

It is presumably considered appropriate to cause harm to persistent transgender adolescents (forced to experience the distress of undergoing the early stages of natal puberty before eligibility for blockers) in order to benefit those youth for whom early puberty results in reduced dysphoria and a cisgender outcome (without need for blockers). We’ll put aside for now the clear prioritisation of the well-being of cisgender youth over the well-being of transgender youth.

For this approach to be at all valid, and for the harm to persistent transgender adolescents to be justified, it must be underpinned by robust evidence that significant numbers of children who are indistinguishable from them pre-puberty, desist during the very early stages (tanner 1-2) of puberty. Where is this evidence? This evidence is not provided in the Endocrine Guidance.

We would argue that there is a significant difference between an approach that says “for transgender children we will suppress puberty as soon as it begins if a child with a consistent, persistent transgender identity expresses distress at the idea of natal puberty”, and an approach that says “all transgender children will be required to go through at least some of their natal puberty, and only once clinicians notice their increased distress at actual physical changes will we consider them eligible for puberty blockers”. The latter approach surely can only be justified if there is robust evidence for this – otherwise a) it perpetuates the idea that children cannot be considered trans until after puberty b) it imposes stress on children and families as they receive no reassurance that blockers will be offered and c) it imposes distress on trans adolescents who are forced to undergo the early physical changes for no purpose.

6. Cross sex hormones prior to age 16

“We recognize that there may be compelling reasons to initiate sex hormone treatment prior to the age of 16 years in some adolescents with GD/ gender incongruence, even though there are minimal published studies of gender-affirming hormone treatments administered before age 13.5 to 14 years.”

Concern 6:

The phrasing above is curious. It mentions “compelling reasons”, but there is no elaboration or discussion on what those reasons may be. In the same sentence it is stated that published data is minimal prior to 13.5 years. But what about for ages 13.5-15.5? We note that in the referenced study (de Vries et al, 2014) the cohort were given cross sex hormones at mean age 16.7, with the youngest age 13.9 years. This study contained no evidence of harm in the younger catchment (though data numbers are small). The references provided do not provide any evidence for negative impacts of cross sex hormone prior to 16 years old, and do provide evidence of the negatives of waiting so long:

“Currently available data from transgender adolescents support treatment with sex hormones starting at age 16 years. However, some patients may incur potential risks by waiting until age 16 years. These include the potential risk to bone health if puberty is suppressed for 6 to 7 years before initiating sex hormones (e.g., if someone reached Tanner stage 2 at age 9-10 years old). Additionally, there may be concerns about inappropriate height and potential harm to mental health (emotional and social isolation) if initiation of secondary sex characteristics must wait until the person has reached 16 years of age. However, only minimal data supporting earlier use of gender-affirming hormones in transgender adolescents currently exist (63). Clearly, long-term studies are needed to determine the optimal age of sex hormone treatment in GD/gender-incongruent adolescents.”

In the absence of evidence for delaying until age 16, we would advise this statement could be more clearly be written as “there is a paucity of studies on prescribing hormones before 16 years old – the few studies available provide no evidence of harm”. We agree more long term study is needed to establish an optimal age for hormone treatment, and appeal to those working in this field to publish existing data.

We also note the lack of any detailed consideration given here to the benefits of peer-concordance, that is, having the same puberty, at the same time, as the adolescent’s peer group in order to reduce both physical dysphoria and wider social stigma.

Conclusion and recommendations:

We welcome this much needed update to the ‘Endocrine clinical guidelines for the treatment of transgender adolescents and adults’.

The finding that there is a “durable biological underpinning to gender identity” represents an important shift from a historical stigmatising psychiatric approach, towards the current affirmative model which acknowledges of a biological basis for gender identity, and respects and affirms an individual’s identity.

In section B we have outlined 7 questions, areas where detail is lacking and guidance unclear. In section C we have outlined 6 areas of concern, where the important recommendations are not grounded in robust evidence. We would welcome any clarifications or responses the authors could provide.

Nonetheless, and in spite of some important concerns, the guidelines are a hugely positive shift from the 2009 document, and represent a step forward in transgender health care.